Expert Opinion on Therapeutic Targets
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MMPs: a novel drug target for schizophrenia Kanwaljit Chopra, Ankita Baveja & Anurag Kuhad To cite this article: Kanwaljit Chopra, Ankita Baveja & Anurag Kuhad (2015) MMPs: a novel drug target for schizophrenia, Expert Opinion on Therapeutic Targets, 19:1, 77-85, DOI: 10.1517/14728222.2014.957672 To link to this article: http://dx.doi.org/10.1517/14728222.2014.957672
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Date: 11 July 2017, At: 02:11
Review
MMPs: a novel drug target for schizophrenia Kanwaljit Chopra, Ankita Baveja & Anurag Kuhad† †
1.
Introduction
2.
Extracellular matrix and schizophrenia
3.
MMPs
4.
Expert opinion
Panjab University, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Pharmacology Research Laboratory, Chandigarh, India
Introduction: Schizophrenia, a multifactorial disorder, is associated with dopaminergic hyperactivity, dysregulated glutamatergic neurotransmission, neuroinflammation and extracellular matrix (ECM) disturbances. MMPs, a group of structurally related proteolytic enzymes, are responsible for remodeling of ECM that maintains synaptic functions and blood--brain barrier (BBB) patency. Overstimulation of MMPs by neuroinflammation triggers ECM abnormalities that directly or indirectly alter neuronal functions like synaptic plasticity and damage to BBB. MMP-mediated ECM abnormality plays a central role in the pathogenesis of schizophrenia. Areas covered: The current review discusses the mechanistic involvement of MMPs in the pathogenesis of schizophrenia and briefly gives an overview on the recent studies on various MMP modulators. Expert opinion: Overexpression of MMPs and imbalance between MMP versus tissue inhibitors of metalloproteinase are associated with various ECM disturbances in the schizophrenic brain. Therefore, MMPs can be projected as potential therapeutic target for treatment and/or prevention of positive, negative and cognitive symptoms of schizophrenia. From past decade, scientific community is focusing on broad spectrum MMP modulators as potential therapeutic moieties for prevention of plethora of neurological, cardiovascular and pulmonary diseases. In future, specific MMP modulators should be tailored to regulate ECM integrity and explored for their pharmacotherapeutic potential in schizophrenia. Keywords: extracellular matrix, glutamate, MMPs, neuroinflammation, schizophrenia Expert Opin. Ther. Targets (2015) 19(1):77-85
1.
Introduction
Schizophrenia is a serious mental disorder with typical onset in the late teens or early adulthood [1], mostly in the age group 15 -- 35 years. It affects about 24 million people wordwide and remains a leading cause of years lived with disability. It affects about seven per thousand of the adult population. Though the incidence is low (3 -- 10,000) but prevalence is high due to chronicity [2]. It is marked by gross distortion from reality, disturbances in thinking, feeling and behavior [3]. The clinical picture of schizophrenia is heterogeneous, but in the vast majority of patients, cognitive dysfunctions are present with adverse impact on daily functioning [1]. Symptoms cluster into three categories: positive or psychotic symptoms (including auditory and visual hallucinations, delusions, conceptual disorganization and thought disorder), negative or deficit symptoms (emotional blunting, social withdrawal, anhedonia, avolition, poverty of thought and content of speech) and cognitive dysfunction (including impaired executive function, working memory, attention and general intellectual functioning) [4,5]. The negative and cognitive symptoms are more persistent and chronic, while the psychotic symptoms have an episodic pattern, which when active, are usually the impetus for hospitalization [5].
10.1517/14728222.2014.957672 © 2015 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631 All rights reserved: reproduction in whole or in part not permitted
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Article highlights. . . .
.
Activated glial cells are potential source of MMPs in CNS. Increased levels of MMP-9 are reported in case of schizophrenia. MMPs can induce schizophrenia by: disrupting blood--brain barrier, degrading extracellular matrix and inducing excitotoxicity by integrin signaling. MMP can be explored as potential therapeutic target for schizophrenia.
This box summarizes key points contained in the article.
The etiology of schizophrenia remains elusive till date [6]. The prefrontal cortex (PFC) and hippocampus are major regions that are affected in schizophrenia, and the transmitters involved include dopamine (DA), glutamate and GABA [7]. Dopaminergic hyperfunction in the limbic system and dopaminergic hypofunction in the frontal cortex as well as glutamatergic hypofunction are known to play important roles in the pathophysiology of schizophrenia [6]. Since NMDA receptors (NMDARs) regulate dopaminergic neurotransmission, therefore hypofunction of NMDARs may be responsible for the abnormal DA activity associated with the symptoms of schizophrenia [8]. NMDAR antagonists appeared to increase the release of glutamate at some synapses, which then abnormally increased glutamate neurotransmission at nonNMDAR, in particular AMPA receptors (AMPARs) [9]. Therefore, the central pathological characteristics seem to be caused by NMDAR hypofunction acting on GABAergic interneurons, followed by the disinhibition of glutamatergic transmission and an overstimulation of non-NMDARs on pyramidal neurons [8]. Disturbed glutamatergic neurotransmission is a central feature in schizophrenia [10]. The process of release, activity as a ligand and reuptake of glutamate involves three distinct cell types: the astrocyte, the presynaptic neuron and the postsynaptic neuron [11]. The availability of glutamate in the synapse to activate its target receptors (ionotropic and metabotropic receptors) is regulated by a family of glutamate transport proteins, the excitatory amino acid transporters (EAATs), localized to the plasma membrane of neurons and astroglial cells. EAAT transports glutamate into astrocytes for conversion into glutamine, which is then released and recycled by neurons to generate glutamate (Figure 1) [12]. 2.
Extracellular matrix and schizophrenia
Extracellular matrix (ECM) is a complex structured network of secreted macromolecules and proteolytic enzymes like MMPs [13]. The major components of the ECM are: i) glycosaminoglycans (GAGs), either bound to proteins, as proteoglycans, or unbound in the form of hyaluronan; ii) fibrous proteins (e.g., collagens and elastin); and iii) adhesive glycoproteins (e.g., fibronectin, laminin and tenascin) and a wide 78
variety of secreted growth factors and other molecules, many of which bind with various affinities to GAGs and other matrix components. The ECM of the CNS is unique in composition and organization as it contains relatively small amounts of fibrous proteins and high amounts of GAGs and is organized around certain neurons to produce specialized condensed ECM, known as perineuronal nets (PNNs) [14]. The adult brain ECM is mainly composed of hyaluronic acid, glycoproteins and chondroitin sulfate proteoglycans (CSPGs) predominantly belonging to the lectican family. Hyaluronan represents the backbone of the brain ECM, while CSPGs are the ‘organizers of the brain ECM’. Other constituents include CSPG phosphacan, tenascins, heparan sulfate proteoglycans, reelin, laminins, thrombospondins, hyaluronidases and proteases [15]. Proteoglycans play a vital role in cell--cell and cell--ECM signaling in the CNS as they can bind diverse extracellular factors, including signaling molecules, membrane proteins and components of the ECM [16]. Two main receptors/adhesion proteins are also involved in the cell--cell and cell--matrix interactions of the blood--brain barrier (BBB): dystroglycan and integrins. They regulate signaling pathways to allow cell adaptations to changes in the microenvironment. They also form a physical link between the ECM and the cytoskeleton, thereby anchoring the cells in place and regulating their motility [17]. ECM plays a vital role in the structure and development of tissues; it provides mechanical strength, acts as a template for cell growth and influences cell behaviors such as migration, adhesion, proliferation and differentiation [13]. ECM also acts as a reservoir of biologically active molecules such as growth factors. Some of the components of ECM can express various essential biological functions on proteolysis. Hence, the degradation of ECM components by MMPs can alter cellular behavior and phenotypes [18].
Pathological involvement of ECM components in schizophrenia
2.1
CSPGs, the main component of brain ECM, expressed by subpopulation of astrocytes in the human amygdala are involved in the pathophysiology of schizophrenia [10]. Marked increase of CSPG-positive glial cells and reduction of CSPG-positive PNNs were also detected in the medial temporal lobe of subjects with schizophrenia along with marked decrease in PNN formation. CSPG interaction with glutamatergic, GABAergic and dopaminergic systems includes CSPG guidance of dopaminergic axons as well as glutamatergic and GABAergic modulation of CSPG expression and PNN formation [19]. CSPGs mediate the astroglial influences on synapse formation and stability and are highly concentrated in PNNs. At synapses, PNNs act as diffusion barriers for extracellular signaling molecules including neurotransmitters and have a role in stabilizing synapses and in synaptic plasticity [19,20]. The degree of ECM viscosity and the interactions between the negatively charged GAG proteoglycan chains and
Expert Opin. Ther. Targets (2015) 19(1)
MMPs: a novel drug target for schizophrenia
NMDAR hypofunction on GABAnergic neurons
Decreased GABAnergic inhibition
More glutamate release
Overstimulation of dopaminergic neurons
Overstimulation of non-NMDARs on pyramidal neurons
Excessive dopamine release
Excitotoxicity
Schizophrenia
Figure 1. A schematic presentation of pathogenesis of schizophrenia. NMDARs: NMDA receptors.
Beneficial actions
• Clearance of debris following injury • Remodeling of ECM for cell migration and axonal elongation • Release of growth factors anchored on the ECM • Angiogenesis • Myelin formation
Undesirable effects
• Breakdown of the blood-brain barrier • Demyelination • Cytokine production and propagation of an inflammatory response • Tumor invasion, metastasis and angiogenesis • Inappropriate degradation of extracellular matrix leading to alteration of structural integrity
Figure 2. Important role of MMPs in CNS. ECM: Extracellular matrix.
glutamate, which is itself negatively charged, control glutamate diffusion in the extracellular space. In early developmental stages, the extracellular concentration of glutamate regulates the synapse formation. Once a synapse is formed, its stabilization and maturation depend on glutamate concentration within the synaptic cleft, as well as on the availability of glutamate receptors to individual synapses [15]. Hyaluronan containing ECM restricts lateral mobility of neurotransmitter receptors. Lateral diffusion of AMPARs is accelerated after removal of the hyaluronanbased ECM [20]. This increases availability of AMPARs and ultimately their overstimulation, which is involved in pathogenesis of schizophrenia. Decreased reelin gene expression has also been observed in schizophrenia and other major psychiatric diseases [21]. It controls maturational changes in somatic NMDAR subunit composition [22]. Thus, alteration
in ECM composition can affect glutamatergic neurotransmission and synaptic plasticity. 3.
MMPs
MMPs, also known as matrixins, are a family of zinccontaining endopeptidases, which have the capacity to degrade ECM components and alter biological functions of ECM [23]. Apart from ECM degradation, MMPs are associated with a variety of normal and pathological conditions [24] as they can control activation of death receptors, growth factors and various other signaling molecules [25]. They are linked to various physiological activities in the CNS such as myelin formation, axonal growth, angiogenesis and regeneration (Figure 2) [26]. MMPs can induce inflammation as they can regulate transmigration of inflammatory cells from
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Table 1. Classification of MMPs. Groups Collagenases Gelatinases Stromelysins Matrilysins Membrane-type MMPs
Others
Type of MMP MMP-1, MMP-8, MMP-13, MMP-18 Gelatinase A (MMP-2), gelatinase B (MMP-9) Stromelysin 1 (MMP-3), stromelysin 2 (MMP-10), stromelysin 3 (MMP-11) Matrilysin 1 (MMP-7), matrilysin 2 (MMP-26) Type I transmembrane proteins (MMP-14, MMP-15, MMP-16, and MMP-24), glycosylphosphatidylinositol (GPI)-anchored proteins (MMP-17 and MMP-25) Metalloelastase (MMP-12), MMP-19, enamelysin (MMP-20), XMMP (Xenopus) (MMP-21), CA-MMP (MMP-23), CMMP (Gallus)(MMP-27), epilysin (MMP-28)
vasculature to the site of inflammation in tissue (Figure 2). They also regulate the recruitment and influx of inflammatory cells to the site of inflammation by processing ECM components, growth factors, cytokines and chemokines. MMP levels are overexpressed in case of inflammation [27]. On the basis of substrate specificity, sequence similarity and domain organization, vertebrate MMPs can be divided into six groups (Table 1) [28]. All of the cell types that exist in the CNS are potential sources of MMPs. In vitro, neurons, astrocytes, microglia and oligodendrocytes express various MMP family members [29]. MMPs are secreted as latent enzymes and require activation [25]. Many MMP genes are inducible by a wide variety of effectors, including growth factors, cytokines such as TNF-a, IL-1b, chemical agents, physical stress, oncogene products and interestingly, cell--cell or cell--ECM interaction [30]. The promoter regions of the inducible genes that encode MMPs generally contain binding sites for transcription factors such as activator protein 1 and NF-kB, which are responsive to oncogenes and cytokines. TNF-a and IL-1b induce transcription of MMP-3 and MMP-9, which are involved in neuroinflammation. MMP-9 also gets activated by other mechanisms such as other proteases (MMP-3) and free radicals (nitric oxide, which acts through N-nitrosylation) (Figure 3) [25]. Pathological involvement of MMPs in schizophrenia 3.1.1 Clinical evidences for involvement of MMPs in schizophrenia 3.1
Domenici et al. studied plasma protein biomarkers in schizophrenic patients and controls, which were subjected to multi-analyte profiling allowing the evaluation of up to 79 proteins, suggested to be involved in the pathophysiology of schizophrenia. They found a sharp rise in levels of MMP-9 in schizophrenic patients [31]. Yamamori et al. have 80
also reported an increase in serum levels of MMP-9 in schizophrenic patients. Genetic variants of MMP-3 gene are associated with schizophrenia [32]. Kucukali et al. reported increased MMP-3 activity in patients with schizophrenia [33]. Induction of MMPs in schizophrenia One of the prototypical destructive events in the human brain, initiated by the release of inflammatory cytokines and ending with tissue destruction, is production of MMPs [29]. Neuroinflammation plays a putative role in schizophrenia [6]. CNS injury, brain trauma, ischemic injuries, immunological reactions and infections can also promote neuroinflammation [25]. The invading T cells during CNS injury may release pro-inflammatory cytokines that activate glial cells (microglia and astrocytes), which control the expression and secretion of MMPs [26]. Microglial cells are the resident immune system phagocytic cells within the brain and spinal cord, and they respond rapidly for neural protection or healing after injury [34]. After CNS injury in adults, microglial cells get activated, adopt an amoeboid shape and can migrate over long distances [35]. Microglial activation is indicated in the course of schizophrenia. NMDAR antagonists such as phencyclidine, ketamine and MK-801, which offer an appropriate animal model of schizophrenia, are known to induce microglial activation [6,36]. Microglia are the primary reservoirs of proinflammatory cytokines such as IL-6, TNF-a and IFN-g [6]. Microglia upon overactivation release cytotoxic factors (e.g., pro-inflammatory cytokines, kynurenines, nitric oxide and reactive oxygen species) [37]. Activated microglia also produce MMPs at the site of inflammation [26]. Several inflammatory cytokines (IL-1a, IL- 1band IL-6) can induce or upregulate the transcription of MMP genes [29]. Astrocytes are also one of the main sources of MMPs in physiological and postlesional conditions [38]. Astrocytes are important for neurotransmitter regulation, ion homeostasis, BBB maintenance and the production of ECM molecules that form basal lamina and PNN [34]. Astrocytes are crucial for glutamate homeostasis in the brain and it has a significant role in the pathophysiology of schizophrenia [10]. MMPs are constitutively expressed by quiescent astrocytes and upregulated in reactive astrocytes under pathological conditions (Figure 3) [38]. 3.1.2
Mechanistic role of MMPs in schizophrenia MMPs can potentially signal through a variety of mechanisms. Since MMPs are involved in neuroinflammation, they can directly or indirectly effect neuronal function [39]. MMP cleavage can activate cytokines and growth factors by processing proforms into active forms such as the pro-inflammatory cytokine TNF-a and neurotrophins. Several MMPs can cleave soluble recombinant pro-TNF-a in vitro. Cleavage of membranebound pro-TNF-a by membrane-type 4 (MT-4)-MMP in COS-7 cells converts it into a soluble pleiotrophic cytokine. The activation and release of TNF-a in the brain can have significant effects on synaptic activity. Glial-derived TNF-a increases the surface expression of AMPARs in both cultured 3.1.3
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MMPs: a novel drug target for schizophrenia
Increased circulating inflammatory cytokines
BBB disruption
Increased invasion of inflammatory T cells into brain
Proinflammatory cytokines
ROS
NMDAR antagonists
Activate glial cells (astrocytes & microglia)
Cytokines IL-1β IL-6 TNF-α
Free radicals NO O2ONOO-
MMPs MMP-9 MMP-3 MMP-2
Schizophrenia
Figure 3. Implications of MMPs in pathogenic cascade of schizophrenia. BBB: Blood--brain barrier; NMDAR: NMDA receptor; ROP: Reactive oxygen species.
hippocampal neurons and acute hippocampal slices (Figure 4) [40]. The plasma levels of IL-1 and IL-1 receptor antagonist (IL-1RA) are increased in patients with schizophrenia [41]. MMP-2, 3 and 9 are involved in proteolytic processing of IL1-b from its precursor form to an active form [42]. Increased IL-6 levels have also been reported in schizophrenic patients, as evidenced by a meta-analysis of 19 studies, including 1219 patients [43]. Kubistova et al. also showed significant increased plasma levels of IL-6 and TNF-a in patients [44]. MMPs are also involved in degradation of CSPGs, major component of ECM [45]. Reduced CSPGs levels have been found in PNN in the brain of schizophrenic patients [19]. MMP-9 degrades tight-junction proteins, regulates NMDA receptor signaling and synaptic remodeling, also implicating this proteinase in the mechanisms of long-term potentiation. MMP-9 activation in astrocytes can be induced by oxidative stress, thrombin, TNF-a or tissue plasminogen activator, and involves activation of MAPKs [46]. MMP-9 also plays an essential role in the breakdown of ECM molecules at the BBB. This together with locally elevated levels of the chemokine IL-8, greatly facilitates the transmigration of activated inflammatory cells across the endothelium [29]. Since MMP-9 influences hippocampal and prefrontal cortical activity, therefore polymorphism of the MMP-9 gene can be associated with the pathogenesis of schizophrenia, a condition in which PFC impairment is one of the most common pathological factors [47]. Rybakowski et al. genotyped a functional MMP-9
polymorphism in a large group of 442 schizophrenia patients and compared it with that of 558 healthy control subjects and concluded that MMP-9 gene is involved in pathogenesis of schizophrenia [48]. Han et al. also investigated a series of Chinese patients with schizophrenia to determine whether the polymorphism in MMP-9 gene is a risk factor for schizophrenia and reported that the C(-1562)T polymorphism in MMP-9 is likely to constitute a risk modifier for schizophrenia in China [49]. A recent meta-analysis reported that peripheral brain-derived neurotrophic factor (BDNF) levels were reduced and MMP-9 levels were increased in schizophrenia. MMP-9 plays a role in the conversion of proBDNF to mature BDNF. In patients with schizophrenia, MMP-9 might be induced to recover the decreased mature BDNF. These findings proposed that plasma levels of MMP-9 can be a useful biomarker for assessing pathological event in brain [32]. MMP-9 has been shown to act via integrin signaling, which also plays a role in NMDAR synaptic transmission and NMDAR-dependent plasticity [50]. MMP-9 may exert its effects on integrins through the cleavage of laminin or other ECM components that can then induce integrin signaling (Figure 4) [40]. Integrin activation by ECM ligands affects key cellular processes, such as survival, proliferation, differentiation and migration through signaling pathways, such as focal adhesion kinase/c-Jun N-terminal kinase (FAK/JNK), Ras/extracellular signal-regulated kinases (ERK) (MAP kinase) and the small guanosine-5¢-triphosphatases [16]. MMP-9-driven release of ECM components may act as a ligand for integrins
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Glutamine (Gln)
Glutamate
Glutaminase
Presynaptic neuron
Reelin
Glutamate (Glu)
EAAT
Astrocytes
Gln mGLuR
Microglia mGLuR
MMPs
Gln Glutamine synthase Glu
MMPs TNF-α
Integrin Glu
mGLuR AMPA R
NMDA R
AMPA-R excitation
NMDA-R hypofunction IL-1R
Postsynaptic neuron
Decreased GABAnergic inhibition
Increased dopamine
IL-1β IL-6
TNFR
TNF-α
Schizophrenia-like symptoms
Figure 4. Molecular mechanism of induction of schizophrenia by MMPs. MMPs released by activated glial cells can signal through various mechanisms: i) activate TNF-a, which can cause overexpression of AMPA receptor and leads to excitotoxic damage; ii) MMPs interfere in integrin signaling by disruption of integrin matrix interactions, direct binding to integrin and generation of matrix fragments that bind to unoccupied integrins; iii) reelin, component of ECM, which induces integrin signaling, is indirectly processed by MMPs; iv) integrin signaling can cause excitotoxic damage to glutamatergic neurons by causing overexcitation of NMDAR, which will create hypoglutamatergic-like state that will ultimately lead to development of schizophrenia; v) MMPs also induce the release of pro-inflammatory cytokines like IL-1b, IL-6 & TNF-a, which will trigger neuroinflammation. EAAT: Excitatory amino acid transporters; ECM: Extracellular matrix; NMDAR: NMDA receptor.
that transfer a signal leading to an increase in lateral diffusion of NMDAR [50]. MMPs may also directly bind to unoccupied integrins and can disrupt integrin matrix interactions, which in turn will influence the activity of intracellular signaling molecules, and in some cases, stimulate cell death through a process known as anoikis [51]. Genes involved in brain developmental pathways, including neuregulin signaling, ERK/MAPK signaling, synaptic long-term potentiation, axonal guidance signaling, integrin signaling and glutamate receptor signaling, were significantly overrepresented in schizophrenia [52]. MMPs also results in activation of proteinase-activated receptors [51] and thus they can cause overexpression of ERK/MAPK signaling, which is also indicated in schizophrenia. MMP-9 is also indirectly involved in proteolytic processing of reelin by regulating the activity of ADAMTS-4 (Figure 4) [53]. Increased MMP-3 activity can modulate synaptic plasticity, spine expression density and dendrite organization by 82
changing ECM of neuron, astrocyte and microglia, which are involved in pathophysiology of schizophrenia. MMP-3 can affect the cytoskeletal structure of neurons by regulating the activity of cell adhesion molecules such as integrins and N-syndecan (syndecan-3) [33]. MMP inhibitors MMP activities are regulated by two major types of endogenous inhibitors: a2-macroglobulin and tissue inhibitors of metalloproteinases (TIMPs) [54]. TIMPs are the most thoroughly studied endogenous MMP inhibitors. Physiological balance between MMPs and TIMPs is considered important to prevent multiple disease conditions. Long-chain fatty acids, epigallocatechin gallate extracted from green tea and flavonoids also belong to natural MMP inhibitors [29]. Three categories of synthetic MMP inhibitors have been developed: the collagen peptidomimetics, the collagen nonpeptidomimetics 3.2
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MMPs: a novel drug target for schizophrenia
and the tetracycline derivates [55]. The first generation of synthetic MMP inhibitors was designed based on mimicking natural peptide substrates, thus so-called peptidomimetic MMP inhibitors. Later on, structure-based MMP inhibitors with a zinc-binding group (ZBG), a backbone that chelates zinc ion in the catalytic core of MMPs, have been extensively developed and tested. Four major ZBGs have been exploited for the development of MMP inhibitors: carboxylates, thiolates, phosphinyls and hydroxamates. Hydroxamates-based MMP inhibitors (batimastat and prinomastat) have been studied most widely [30]. The tetracycline derivates inhibit both the activity and synthesis of MMPs [55] and are only FDA-approved MMP inhibitor [30]. A possible antipsychotic effect of minocycline, which is a potent inhibitor of microglial activation, has also been reported in patients with schizophrenia. Statistically significant and robust clinical improvements with minocycline as an adjunctive therapy to antipsychotics for schizophrenia have been observed [6]. Minocycline has a variety of functions in the CNS such as interacting with brain glutamate and DA neurotransmission and having direct effects on neuronal cells. Rodent studies have revealed that minocycline inhibits microglial activation [2,36,56]. Tetracyclines and their analogs doxycycline and minocycline also inhibit MMPs [57]. Since activated microglia is major source of MMPs, therefore we can assume that MMPs are also involved in pathogenesis of schizophrenia and antipsychotic action of minocycline is also mediated by MMP inhibition. In vitro studies using rat microglial cells have revealed that estradiol inhibits MMP-9 [36]. Estradiol is also effective as adjunctive therapy in treatment of schizophrenia [58] and its action could also be mediated via MMP inhibition. 4.
Expert opinion
MMPs are likely to control various normal physiological processes like tissue remodeling, angiogenesis, BBB patency, synaptic plasticity and myelination by ECM remodeling. Under normal physiological conditions, a precise balance between MMPs and TIMPs exists and that is must for overall growth and development of body. Imbalance between MMPs and TIMPs triggers various pathological changes in the tissue structure and hampers normal physiological processes. Scientific literature contains experimental reports on expression of MMPs and TIMPs in the CNS, including neurons, astrocytes, oligodendrocytes and microglia and their involvement in neurogenesis, axonal guidance, angiogenesis and myelinogenesis. Hyperstimulation of MMPs by various toxins/triggers will lead to structural and functional alterations in neurons and neuronal degeneration, which is hallmark of plethora of neurological disorders. Schizophrenia, a multifactorial disorder, is mainly associated with dopaminergic hyperfunction, disturbed glutamatergic neurotransmission, oxidative stress, neuroinflammation and ECM abnormalities. Currently, the therapeutic strategies
for treatment/prevention of positive, negative and cognitive symptoms of schizophrenia are just focused on regulation of dopaminergic neurotransmission. Out of all mentioned pathogenic factors, ECM abnormality is one major area that remains unexplored for its pharmacotherapeutic potential in schizophrenia. ECM disturbances can affect the integrity of glutamatergic synapses and disrupt blood--brain permeability in schizophrenic patients. Altered glutamatergic integrity creates excitotoxicity that leads to neuronal death and causes various functional abnormalities in schizophrenics. Damage to BBB is the main cause of cerebral delivery of toxins from peripheral circulation and these toxins further precipitate neuronal dysfunction in schizophrenic patients. Therefore, maintenance of glutamatergic transmission and BBB integrity by regulation of ECM disturbances in schizophrenia could be of potential therapeutic interest. Glial cell-mediated altered MMP expression plays a crucial role in the pathogenesis of schizophrenia. One of the major functions of MMP is to hydrolyze ECM, which plays an important part in neuronal regulation, neurotransmitter signaling and synaptic plasticity. Overexpression of MMPs and imbalance between MMP versus TIMP are associated with various ECM disturbances in the schizophrenic brain. Oxidative stress and neuroinflammation can also upregulate MMP expression, which can result in tissue destruction, neuronal death and ECM abnormalities in schizophrenia. Therefore, MMPs can be projected as potential therapeutic target for treatment and/ or prevention of positive, negative and cognitive symptoms of schizophrenia. From past decade, scientific community is focusing on broad spectrum MMP modulators as potential therapeutic moieties for prevention of plethora of neurological, cardiovascular and pulmonary diseases. Since MMPs are also associated with normal physiological and house-keeping functions, therefore specific inhibitors of pathogenic MMPs must be developed so as to prevent the musculoskeletal side effects produced by nonspecific broad spectrum MMP inhibitors. Musculoskeletal syndrome, characterized by joint pain, tenderness and stiffness, is the most common side effect caused by many MMP inhibitors. Although scientists are putting their hardest efforts to develop highly selective and specific MMP inhibitors but doxycycline is the only FDA-approved MMP inhibitor available in the market currently. In future, specific MMP modulators should be tailored to regulate normal physiological remodeling of ECM and explored for their pharmacotherapeutic potential in schizophrenia.
Declaration of interest The authors were supported by University Grants Commission, New Delhi for UGC Start-Up Research Grant for Newly Recruited Faculty sanctioned to A Kuhad. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Affiliation Kanwaljit Chopra1, Ankita Baveja1 & Anurag Kuhad† 2 M Pharm PhD MNASc † Author for correspondence 1 Panjab University, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Pharmacology Research Laboratory, Chandigarh 160 014, India 2 Assistant Professor of Pharmacology, Panjab University, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Pharmacology Research Laboratory, Chandigarh, 160 014, India Tel: +91 9915173064; Fax: +91 172 2534101; E-mail: [email protected]
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MMPs: a novel drug target for schizophrenia Kanwaljit Chopra, Ankita Baveja & Anurag Kuhad To cite this article: Kanwaljit Chopra, Ankita Baveja & Anurag Kuhad (2015) MMPs: a novel drug target for schizophrenia, Expert Opinion on Therapeutic Targets, 19:1, 77-85, DOI: 10.1517/14728222.2014.957672 To link to this article: http://dx.doi.org/10.1517/14728222.2014.957672
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Date: 11 July 2017, At: 02:11
Review
MMPs: a novel drug target for schizophrenia Kanwaljit Chopra, Ankita Baveja & Anurag Kuhad† †
1.
Introduction
2.
Extracellular matrix and schizophrenia
3.
MMPs
4.
Expert opinion
Panjab University, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Pharmacology Research Laboratory, Chandigarh, India
Introduction: Schizophrenia, a multifactorial disorder, is associated with dopaminergic hyperactivity, dysregulated glutamatergic neurotransmission, neuroinflammation and extracellular matrix (ECM) disturbances. MMPs, a group of structurally related proteolytic enzymes, are responsible for remodeling of ECM that maintains synaptic functions and blood--brain barrier (BBB) patency. Overstimulation of MMPs by neuroinflammation triggers ECM abnormalities that directly or indirectly alter neuronal functions like synaptic plasticity and damage to BBB. MMP-mediated ECM abnormality plays a central role in the pathogenesis of schizophrenia. Areas covered: The current review discusses the mechanistic involvement of MMPs in the pathogenesis of schizophrenia and briefly gives an overview on the recent studies on various MMP modulators. Expert opinion: Overexpression of MMPs and imbalance between MMP versus tissue inhibitors of metalloproteinase are associated with various ECM disturbances in the schizophrenic brain. Therefore, MMPs can be projected as potential therapeutic target for treatment and/or prevention of positive, negative and cognitive symptoms of schizophrenia. From past decade, scientific community is focusing on broad spectrum MMP modulators as potential therapeutic moieties for prevention of plethora of neurological, cardiovascular and pulmonary diseases. In future, specific MMP modulators should be tailored to regulate ECM integrity and explored for their pharmacotherapeutic potential in schizophrenia. Keywords: extracellular matrix, glutamate, MMPs, neuroinflammation, schizophrenia Expert Opin. Ther. Targets (2015) 19(1):77-85
1.
Introduction
Schizophrenia is a serious mental disorder with typical onset in the late teens or early adulthood [1], mostly in the age group 15 -- 35 years. It affects about 24 million people wordwide and remains a leading cause of years lived with disability. It affects about seven per thousand of the adult population. Though the incidence is low (3 -- 10,000) but prevalence is high due to chronicity [2]. It is marked by gross distortion from reality, disturbances in thinking, feeling and behavior [3]. The clinical picture of schizophrenia is heterogeneous, but in the vast majority of patients, cognitive dysfunctions are present with adverse impact on daily functioning [1]. Symptoms cluster into three categories: positive or psychotic symptoms (including auditory and visual hallucinations, delusions, conceptual disorganization and thought disorder), negative or deficit symptoms (emotional blunting, social withdrawal, anhedonia, avolition, poverty of thought and content of speech) and cognitive dysfunction (including impaired executive function, working memory, attention and general intellectual functioning) [4,5]. The negative and cognitive symptoms are more persistent and chronic, while the psychotic symptoms have an episodic pattern, which when active, are usually the impetus for hospitalization [5].
10.1517/14728222.2014.957672 © 2015 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631 All rights reserved: reproduction in whole or in part not permitted
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Article highlights. . . .
.
Activated glial cells are potential source of MMPs in CNS. Increased levels of MMP-9 are reported in case of schizophrenia. MMPs can induce schizophrenia by: disrupting blood--brain barrier, degrading extracellular matrix and inducing excitotoxicity by integrin signaling. MMP can be explored as potential therapeutic target for schizophrenia.
This box summarizes key points contained in the article.
The etiology of schizophrenia remains elusive till date [6]. The prefrontal cortex (PFC) and hippocampus are major regions that are affected in schizophrenia, and the transmitters involved include dopamine (DA), glutamate and GABA [7]. Dopaminergic hyperfunction in the limbic system and dopaminergic hypofunction in the frontal cortex as well as glutamatergic hypofunction are known to play important roles in the pathophysiology of schizophrenia [6]. Since NMDA receptors (NMDARs) regulate dopaminergic neurotransmission, therefore hypofunction of NMDARs may be responsible for the abnormal DA activity associated with the symptoms of schizophrenia [8]. NMDAR antagonists appeared to increase the release of glutamate at some synapses, which then abnormally increased glutamate neurotransmission at nonNMDAR, in particular AMPA receptors (AMPARs) [9]. Therefore, the central pathological characteristics seem to be caused by NMDAR hypofunction acting on GABAergic interneurons, followed by the disinhibition of glutamatergic transmission and an overstimulation of non-NMDARs on pyramidal neurons [8]. Disturbed glutamatergic neurotransmission is a central feature in schizophrenia [10]. The process of release, activity as a ligand and reuptake of glutamate involves three distinct cell types: the astrocyte, the presynaptic neuron and the postsynaptic neuron [11]. The availability of glutamate in the synapse to activate its target receptors (ionotropic and metabotropic receptors) is regulated by a family of glutamate transport proteins, the excitatory amino acid transporters (EAATs), localized to the plasma membrane of neurons and astroglial cells. EAAT transports glutamate into astrocytes for conversion into glutamine, which is then released and recycled by neurons to generate glutamate (Figure 1) [12]. 2.
Extracellular matrix and schizophrenia
Extracellular matrix (ECM) is a complex structured network of secreted macromolecules and proteolytic enzymes like MMPs [13]. The major components of the ECM are: i) glycosaminoglycans (GAGs), either bound to proteins, as proteoglycans, or unbound in the form of hyaluronan; ii) fibrous proteins (e.g., collagens and elastin); and iii) adhesive glycoproteins (e.g., fibronectin, laminin and tenascin) and a wide 78
variety of secreted growth factors and other molecules, many of which bind with various affinities to GAGs and other matrix components. The ECM of the CNS is unique in composition and organization as it contains relatively small amounts of fibrous proteins and high amounts of GAGs and is organized around certain neurons to produce specialized condensed ECM, known as perineuronal nets (PNNs) [14]. The adult brain ECM is mainly composed of hyaluronic acid, glycoproteins and chondroitin sulfate proteoglycans (CSPGs) predominantly belonging to the lectican family. Hyaluronan represents the backbone of the brain ECM, while CSPGs are the ‘organizers of the brain ECM’. Other constituents include CSPG phosphacan, tenascins, heparan sulfate proteoglycans, reelin, laminins, thrombospondins, hyaluronidases and proteases [15]. Proteoglycans play a vital role in cell--cell and cell--ECM signaling in the CNS as they can bind diverse extracellular factors, including signaling molecules, membrane proteins and components of the ECM [16]. Two main receptors/adhesion proteins are also involved in the cell--cell and cell--matrix interactions of the blood--brain barrier (BBB): dystroglycan and integrins. They regulate signaling pathways to allow cell adaptations to changes in the microenvironment. They also form a physical link between the ECM and the cytoskeleton, thereby anchoring the cells in place and regulating their motility [17]. ECM plays a vital role in the structure and development of tissues; it provides mechanical strength, acts as a template for cell growth and influences cell behaviors such as migration, adhesion, proliferation and differentiation [13]. ECM also acts as a reservoir of biologically active molecules such as growth factors. Some of the components of ECM can express various essential biological functions on proteolysis. Hence, the degradation of ECM components by MMPs can alter cellular behavior and phenotypes [18].
Pathological involvement of ECM components in schizophrenia
2.1
CSPGs, the main component of brain ECM, expressed by subpopulation of astrocytes in the human amygdala are involved in the pathophysiology of schizophrenia [10]. Marked increase of CSPG-positive glial cells and reduction of CSPG-positive PNNs were also detected in the medial temporal lobe of subjects with schizophrenia along with marked decrease in PNN formation. CSPG interaction with glutamatergic, GABAergic and dopaminergic systems includes CSPG guidance of dopaminergic axons as well as glutamatergic and GABAergic modulation of CSPG expression and PNN formation [19]. CSPGs mediate the astroglial influences on synapse formation and stability and are highly concentrated in PNNs. At synapses, PNNs act as diffusion barriers for extracellular signaling molecules including neurotransmitters and have a role in stabilizing synapses and in synaptic plasticity [19,20]. The degree of ECM viscosity and the interactions between the negatively charged GAG proteoglycan chains and
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MMPs: a novel drug target for schizophrenia
NMDAR hypofunction on GABAnergic neurons
Decreased GABAnergic inhibition
More glutamate release
Overstimulation of dopaminergic neurons
Overstimulation of non-NMDARs on pyramidal neurons
Excessive dopamine release
Excitotoxicity
Schizophrenia
Figure 1. A schematic presentation of pathogenesis of schizophrenia. NMDARs: NMDA receptors.
Beneficial actions
• Clearance of debris following injury • Remodeling of ECM for cell migration and axonal elongation • Release of growth factors anchored on the ECM • Angiogenesis • Myelin formation
Undesirable effects
• Breakdown of the blood-brain barrier • Demyelination • Cytokine production and propagation of an inflammatory response • Tumor invasion, metastasis and angiogenesis • Inappropriate degradation of extracellular matrix leading to alteration of structural integrity
Figure 2. Important role of MMPs in CNS. ECM: Extracellular matrix.
glutamate, which is itself negatively charged, control glutamate diffusion in the extracellular space. In early developmental stages, the extracellular concentration of glutamate regulates the synapse formation. Once a synapse is formed, its stabilization and maturation depend on glutamate concentration within the synaptic cleft, as well as on the availability of glutamate receptors to individual synapses [15]. Hyaluronan containing ECM restricts lateral mobility of neurotransmitter receptors. Lateral diffusion of AMPARs is accelerated after removal of the hyaluronanbased ECM [20]. This increases availability of AMPARs and ultimately their overstimulation, which is involved in pathogenesis of schizophrenia. Decreased reelin gene expression has also been observed in schizophrenia and other major psychiatric diseases [21]. It controls maturational changes in somatic NMDAR subunit composition [22]. Thus, alteration
in ECM composition can affect glutamatergic neurotransmission and synaptic plasticity. 3.
MMPs
MMPs, also known as matrixins, are a family of zinccontaining endopeptidases, which have the capacity to degrade ECM components and alter biological functions of ECM [23]. Apart from ECM degradation, MMPs are associated with a variety of normal and pathological conditions [24] as they can control activation of death receptors, growth factors and various other signaling molecules [25]. They are linked to various physiological activities in the CNS such as myelin formation, axonal growth, angiogenesis and regeneration (Figure 2) [26]. MMPs can induce inflammation as they can regulate transmigration of inflammatory cells from
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Table 1. Classification of MMPs. Groups Collagenases Gelatinases Stromelysins Matrilysins Membrane-type MMPs
Others
Type of MMP MMP-1, MMP-8, MMP-13, MMP-18 Gelatinase A (MMP-2), gelatinase B (MMP-9) Stromelysin 1 (MMP-3), stromelysin 2 (MMP-10), stromelysin 3 (MMP-11) Matrilysin 1 (MMP-7), matrilysin 2 (MMP-26) Type I transmembrane proteins (MMP-14, MMP-15, MMP-16, and MMP-24), glycosylphosphatidylinositol (GPI)-anchored proteins (MMP-17 and MMP-25) Metalloelastase (MMP-12), MMP-19, enamelysin (MMP-20), XMMP (Xenopus) (MMP-21), CA-MMP (MMP-23), CMMP (Gallus)(MMP-27), epilysin (MMP-28)
vasculature to the site of inflammation in tissue (Figure 2). They also regulate the recruitment and influx of inflammatory cells to the site of inflammation by processing ECM components, growth factors, cytokines and chemokines. MMP levels are overexpressed in case of inflammation [27]. On the basis of substrate specificity, sequence similarity and domain organization, vertebrate MMPs can be divided into six groups (Table 1) [28]. All of the cell types that exist in the CNS are potential sources of MMPs. In vitro, neurons, astrocytes, microglia and oligodendrocytes express various MMP family members [29]. MMPs are secreted as latent enzymes and require activation [25]. Many MMP genes are inducible by a wide variety of effectors, including growth factors, cytokines such as TNF-a, IL-1b, chemical agents, physical stress, oncogene products and interestingly, cell--cell or cell--ECM interaction [30]. The promoter regions of the inducible genes that encode MMPs generally contain binding sites for transcription factors such as activator protein 1 and NF-kB, which are responsive to oncogenes and cytokines. TNF-a and IL-1b induce transcription of MMP-3 and MMP-9, which are involved in neuroinflammation. MMP-9 also gets activated by other mechanisms such as other proteases (MMP-3) and free radicals (nitric oxide, which acts through N-nitrosylation) (Figure 3) [25]. Pathological involvement of MMPs in schizophrenia 3.1.1 Clinical evidences for involvement of MMPs in schizophrenia 3.1
Domenici et al. studied plasma protein biomarkers in schizophrenic patients and controls, which were subjected to multi-analyte profiling allowing the evaluation of up to 79 proteins, suggested to be involved in the pathophysiology of schizophrenia. They found a sharp rise in levels of MMP-9 in schizophrenic patients [31]. Yamamori et al. have 80
also reported an increase in serum levels of MMP-9 in schizophrenic patients. Genetic variants of MMP-3 gene are associated with schizophrenia [32]. Kucukali et al. reported increased MMP-3 activity in patients with schizophrenia [33]. Induction of MMPs in schizophrenia One of the prototypical destructive events in the human brain, initiated by the release of inflammatory cytokines and ending with tissue destruction, is production of MMPs [29]. Neuroinflammation plays a putative role in schizophrenia [6]. CNS injury, brain trauma, ischemic injuries, immunological reactions and infections can also promote neuroinflammation [25]. The invading T cells during CNS injury may release pro-inflammatory cytokines that activate glial cells (microglia and astrocytes), which control the expression and secretion of MMPs [26]. Microglial cells are the resident immune system phagocytic cells within the brain and spinal cord, and they respond rapidly for neural protection or healing after injury [34]. After CNS injury in adults, microglial cells get activated, adopt an amoeboid shape and can migrate over long distances [35]. Microglial activation is indicated in the course of schizophrenia. NMDAR antagonists such as phencyclidine, ketamine and MK-801, which offer an appropriate animal model of schizophrenia, are known to induce microglial activation [6,36]. Microglia are the primary reservoirs of proinflammatory cytokines such as IL-6, TNF-a and IFN-g [6]. Microglia upon overactivation release cytotoxic factors (e.g., pro-inflammatory cytokines, kynurenines, nitric oxide and reactive oxygen species) [37]. Activated microglia also produce MMPs at the site of inflammation [26]. Several inflammatory cytokines (IL-1a, IL- 1band IL-6) can induce or upregulate the transcription of MMP genes [29]. Astrocytes are also one of the main sources of MMPs in physiological and postlesional conditions [38]. Astrocytes are important for neurotransmitter regulation, ion homeostasis, BBB maintenance and the production of ECM molecules that form basal lamina and PNN [34]. Astrocytes are crucial for glutamate homeostasis in the brain and it has a significant role in the pathophysiology of schizophrenia [10]. MMPs are constitutively expressed by quiescent astrocytes and upregulated in reactive astrocytes under pathological conditions (Figure 3) [38]. 3.1.2
Mechanistic role of MMPs in schizophrenia MMPs can potentially signal through a variety of mechanisms. Since MMPs are involved in neuroinflammation, they can directly or indirectly effect neuronal function [39]. MMP cleavage can activate cytokines and growth factors by processing proforms into active forms such as the pro-inflammatory cytokine TNF-a and neurotrophins. Several MMPs can cleave soluble recombinant pro-TNF-a in vitro. Cleavage of membranebound pro-TNF-a by membrane-type 4 (MT-4)-MMP in COS-7 cells converts it into a soluble pleiotrophic cytokine. The activation and release of TNF-a in the brain can have significant effects on synaptic activity. Glial-derived TNF-a increases the surface expression of AMPARs in both cultured 3.1.3
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MMPs: a novel drug target for schizophrenia
Increased circulating inflammatory cytokines
BBB disruption
Increased invasion of inflammatory T cells into brain
Proinflammatory cytokines
ROS
NMDAR antagonists
Activate glial cells (astrocytes & microglia)
Cytokines IL-1β IL-6 TNF-α
Free radicals NO O2ONOO-
MMPs MMP-9 MMP-3 MMP-2
Schizophrenia
Figure 3. Implications of MMPs in pathogenic cascade of schizophrenia. BBB: Blood--brain barrier; NMDAR: NMDA receptor; ROP: Reactive oxygen species.
hippocampal neurons and acute hippocampal slices (Figure 4) [40]. The plasma levels of IL-1 and IL-1 receptor antagonist (IL-1RA) are increased in patients with schizophrenia [41]. MMP-2, 3 and 9 are involved in proteolytic processing of IL1-b from its precursor form to an active form [42]. Increased IL-6 levels have also been reported in schizophrenic patients, as evidenced by a meta-analysis of 19 studies, including 1219 patients [43]. Kubistova et al. also showed significant increased plasma levels of IL-6 and TNF-a in patients [44]. MMPs are also involved in degradation of CSPGs, major component of ECM [45]. Reduced CSPGs levels have been found in PNN in the brain of schizophrenic patients [19]. MMP-9 degrades tight-junction proteins, regulates NMDA receptor signaling and synaptic remodeling, also implicating this proteinase in the mechanisms of long-term potentiation. MMP-9 activation in astrocytes can be induced by oxidative stress, thrombin, TNF-a or tissue plasminogen activator, and involves activation of MAPKs [46]. MMP-9 also plays an essential role in the breakdown of ECM molecules at the BBB. This together with locally elevated levels of the chemokine IL-8, greatly facilitates the transmigration of activated inflammatory cells across the endothelium [29]. Since MMP-9 influences hippocampal and prefrontal cortical activity, therefore polymorphism of the MMP-9 gene can be associated with the pathogenesis of schizophrenia, a condition in which PFC impairment is one of the most common pathological factors [47]. Rybakowski et al. genotyped a functional MMP-9
polymorphism in a large group of 442 schizophrenia patients and compared it with that of 558 healthy control subjects and concluded that MMP-9 gene is involved in pathogenesis of schizophrenia [48]. Han et al. also investigated a series of Chinese patients with schizophrenia to determine whether the polymorphism in MMP-9 gene is a risk factor for schizophrenia and reported that the C(-1562)T polymorphism in MMP-9 is likely to constitute a risk modifier for schizophrenia in China [49]. A recent meta-analysis reported that peripheral brain-derived neurotrophic factor (BDNF) levels were reduced and MMP-9 levels were increased in schizophrenia. MMP-9 plays a role in the conversion of proBDNF to mature BDNF. In patients with schizophrenia, MMP-9 might be induced to recover the decreased mature BDNF. These findings proposed that plasma levels of MMP-9 can be a useful biomarker for assessing pathological event in brain [32]. MMP-9 has been shown to act via integrin signaling, which also plays a role in NMDAR synaptic transmission and NMDAR-dependent plasticity [50]. MMP-9 may exert its effects on integrins through the cleavage of laminin or other ECM components that can then induce integrin signaling (Figure 4) [40]. Integrin activation by ECM ligands affects key cellular processes, such as survival, proliferation, differentiation and migration through signaling pathways, such as focal adhesion kinase/c-Jun N-terminal kinase (FAK/JNK), Ras/extracellular signal-regulated kinases (ERK) (MAP kinase) and the small guanosine-5¢-triphosphatases [16]. MMP-9-driven release of ECM components may act as a ligand for integrins
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Glutamine (Gln)
Glutamate
Glutaminase
Presynaptic neuron
Reelin
Glutamate (Glu)
EAAT
Astrocytes
Gln mGLuR
Microglia mGLuR
MMPs
Gln Glutamine synthase Glu
MMPs TNF-α
Integrin Glu
mGLuR AMPA R
NMDA R
AMPA-R excitation
NMDA-R hypofunction IL-1R
Postsynaptic neuron
Decreased GABAnergic inhibition
Increased dopamine
IL-1β IL-6
TNFR
TNF-α
Schizophrenia-like symptoms
Figure 4. Molecular mechanism of induction of schizophrenia by MMPs. MMPs released by activated glial cells can signal through various mechanisms: i) activate TNF-a, which can cause overexpression of AMPA receptor and leads to excitotoxic damage; ii) MMPs interfere in integrin signaling by disruption of integrin matrix interactions, direct binding to integrin and generation of matrix fragments that bind to unoccupied integrins; iii) reelin, component of ECM, which induces integrin signaling, is indirectly processed by MMPs; iv) integrin signaling can cause excitotoxic damage to glutamatergic neurons by causing overexcitation of NMDAR, which will create hypoglutamatergic-like state that will ultimately lead to development of schizophrenia; v) MMPs also induce the release of pro-inflammatory cytokines like IL-1b, IL-6 & TNF-a, which will trigger neuroinflammation. EAAT: Excitatory amino acid transporters; ECM: Extracellular matrix; NMDAR: NMDA receptor.
that transfer a signal leading to an increase in lateral diffusion of NMDAR [50]. MMPs may also directly bind to unoccupied integrins and can disrupt integrin matrix interactions, which in turn will influence the activity of intracellular signaling molecules, and in some cases, stimulate cell death through a process known as anoikis [51]. Genes involved in brain developmental pathways, including neuregulin signaling, ERK/MAPK signaling, synaptic long-term potentiation, axonal guidance signaling, integrin signaling and glutamate receptor signaling, were significantly overrepresented in schizophrenia [52]. MMPs also results in activation of proteinase-activated receptors [51] and thus they can cause overexpression of ERK/MAPK signaling, which is also indicated in schizophrenia. MMP-9 is also indirectly involved in proteolytic processing of reelin by regulating the activity of ADAMTS-4 (Figure 4) [53]. Increased MMP-3 activity can modulate synaptic plasticity, spine expression density and dendrite organization by 82
changing ECM of neuron, astrocyte and microglia, which are involved in pathophysiology of schizophrenia. MMP-3 can affect the cytoskeletal structure of neurons by regulating the activity of cell adhesion molecules such as integrins and N-syndecan (syndecan-3) [33]. MMP inhibitors MMP activities are regulated by two major types of endogenous inhibitors: a2-macroglobulin and tissue inhibitors of metalloproteinases (TIMPs) [54]. TIMPs are the most thoroughly studied endogenous MMP inhibitors. Physiological balance between MMPs and TIMPs is considered important to prevent multiple disease conditions. Long-chain fatty acids, epigallocatechin gallate extracted from green tea and flavonoids also belong to natural MMP inhibitors [29]. Three categories of synthetic MMP inhibitors have been developed: the collagen peptidomimetics, the collagen nonpeptidomimetics 3.2
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MMPs: a novel drug target for schizophrenia
and the tetracycline derivates [55]. The first generation of synthetic MMP inhibitors was designed based on mimicking natural peptide substrates, thus so-called peptidomimetic MMP inhibitors. Later on, structure-based MMP inhibitors with a zinc-binding group (ZBG), a backbone that chelates zinc ion in the catalytic core of MMPs, have been extensively developed and tested. Four major ZBGs have been exploited for the development of MMP inhibitors: carboxylates, thiolates, phosphinyls and hydroxamates. Hydroxamates-based MMP inhibitors (batimastat and prinomastat) have been studied most widely [30]. The tetracycline derivates inhibit both the activity and synthesis of MMPs [55] and are only FDA-approved MMP inhibitor [30]. A possible antipsychotic effect of minocycline, which is a potent inhibitor of microglial activation, has also been reported in patients with schizophrenia. Statistically significant and robust clinical improvements with minocycline as an adjunctive therapy to antipsychotics for schizophrenia have been observed [6]. Minocycline has a variety of functions in the CNS such as interacting with brain glutamate and DA neurotransmission and having direct effects on neuronal cells. Rodent studies have revealed that minocycline inhibits microglial activation [2,36,56]. Tetracyclines and their analogs doxycycline and minocycline also inhibit MMPs [57]. Since activated microglia is major source of MMPs, therefore we can assume that MMPs are also involved in pathogenesis of schizophrenia and antipsychotic action of minocycline is also mediated by MMP inhibition. In vitro studies using rat microglial cells have revealed that estradiol inhibits MMP-9 [36]. Estradiol is also effective as adjunctive therapy in treatment of schizophrenia [58] and its action could also be mediated via MMP inhibition. 4.
Expert opinion
MMPs are likely to control various normal physiological processes like tissue remodeling, angiogenesis, BBB patency, synaptic plasticity and myelination by ECM remodeling. Under normal physiological conditions, a precise balance between MMPs and TIMPs exists and that is must for overall growth and development of body. Imbalance between MMPs and TIMPs triggers various pathological changes in the tissue structure and hampers normal physiological processes. Scientific literature contains experimental reports on expression of MMPs and TIMPs in the CNS, including neurons, astrocytes, oligodendrocytes and microglia and their involvement in neurogenesis, axonal guidance, angiogenesis and myelinogenesis. Hyperstimulation of MMPs by various toxins/triggers will lead to structural and functional alterations in neurons and neuronal degeneration, which is hallmark of plethora of neurological disorders. Schizophrenia, a multifactorial disorder, is mainly associated with dopaminergic hyperfunction, disturbed glutamatergic neurotransmission, oxidative stress, neuroinflammation and ECM abnormalities. Currently, the therapeutic strategies
for treatment/prevention of positive, negative and cognitive symptoms of schizophrenia are just focused on regulation of dopaminergic neurotransmission. Out of all mentioned pathogenic factors, ECM abnormality is one major area that remains unexplored for its pharmacotherapeutic potential in schizophrenia. ECM disturbances can affect the integrity of glutamatergic synapses and disrupt blood--brain permeability in schizophrenic patients. Altered glutamatergic integrity creates excitotoxicity that leads to neuronal death and causes various functional abnormalities in schizophrenics. Damage to BBB is the main cause of cerebral delivery of toxins from peripheral circulation and these toxins further precipitate neuronal dysfunction in schizophrenic patients. Therefore, maintenance of glutamatergic transmission and BBB integrity by regulation of ECM disturbances in schizophrenia could be of potential therapeutic interest. Glial cell-mediated altered MMP expression plays a crucial role in the pathogenesis of schizophrenia. One of the major functions of MMP is to hydrolyze ECM, which plays an important part in neuronal regulation, neurotransmitter signaling and synaptic plasticity. Overexpression of MMPs and imbalance between MMP versus TIMP are associated with various ECM disturbances in the schizophrenic brain. Oxidative stress and neuroinflammation can also upregulate MMP expression, which can result in tissue destruction, neuronal death and ECM abnormalities in schizophrenia. Therefore, MMPs can be projected as potential therapeutic target for treatment and/ or prevention of positive, negative and cognitive symptoms of schizophrenia. From past decade, scientific community is focusing on broad spectrum MMP modulators as potential therapeutic moieties for prevention of plethora of neurological, cardiovascular and pulmonary diseases. Since MMPs are also associated with normal physiological and house-keeping functions, therefore specific inhibitors of pathogenic MMPs must be developed so as to prevent the musculoskeletal side effects produced by nonspecific broad spectrum MMP inhibitors. Musculoskeletal syndrome, characterized by joint pain, tenderness and stiffness, is the most common side effect caused by many MMP inhibitors. Although scientists are putting their hardest efforts to develop highly selective and specific MMP inhibitors but doxycycline is the only FDA-approved MMP inhibitor available in the market currently. In future, specific MMP modulators should be tailored to regulate normal physiological remodeling of ECM and explored for their pharmacotherapeutic potential in schizophrenia.
Declaration of interest The authors were supported by University Grants Commission, New Delhi for UGC Start-Up Research Grant for Newly Recruited Faculty sanctioned to A Kuhad. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Affiliation Kanwaljit Chopra1, Ankita Baveja1 & Anurag Kuhad† 2 M Pharm PhD MNASc † Author for correspondence 1 Panjab University, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Pharmacology Research Laboratory, Chandigarh 160 014, India 2 Assistant Professor of Pharmacology, Panjab University, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Pharmacology Research Laboratory, Chandigarh, 160 014, India Tel: +91 9915173064; Fax: +91 172 2534101; E-mail: [email protected]
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